Age-related hearing loss (Presbycusis) is a major health concern for the elderly population. Loss ofspiral ganglion neurons (SGNs) is consistently associated with Presbycusis. The sequence of causative molecular events for age-related loss of SGNs is unknown. This proposal focuses on possible roles of Neuregulin-1 may have on this aging process. My recent work revealed: (a) the cytoplasmic domain of Neuregulin-I (NRG-CD) is highly expressed in SGNs; (b) NRG-CD can translocate into the nucleus and regulate gene expression including that of apoptotic genes; and (c) during aging there is a correlation between nuclear translocation of NRG-CD and up-regulation of BAK, a pro-apoptotic gene. The general hypothesis is that NRG-CD plays an essential role in age-related loss of SGNs. I will first determine the temporal profile of NRG-CD nuclear translocation and subsequent gene expression profile during age-related SGN loss. I will then assess how direct manipulation of nuclear NRG-CD in vivo influences age-related loss of SGNs. Furthermore, I will decipher gene expression profiles directly regulated by NRG-CD nuclear translocation during age-related loss of SGNs. The ultimate goal of this research is to develop methods for prevention and treatment of age-related loss of SGNs based on identifying molecular candidates involved in this aging process. The career development of the candidate during this award will be provided by the mentor: Loma Role (for neuroscience and physiological expertise), and two outstanding co-mentors: Ronald Liem (for aging and molecular expertise), and Robin Davis (auditory neuroscience expertise). In addition, collaborative relationships with three experts on transgenic and microarray methods have also been arranged with Drs. Richard Axel, Rene Hen, and Anthony Ferrante. From the conduct of this research under their supervision, the candidate will expand his capabilities with advanced methods of transgenic and DNA microarray technologies, acquire new skills in molecular and genetic analysis of aging. The goal of this award is to elucidate the role of NRG-CD in age-related loss of SGNs as well as to provide the candidate with the continuity of support necessary to develop into an independent investigator.